RESUMO
Microglia-mediated neuroinflammation plays a critical role in the occurrence and progression of Alzheimer's disease (AD). In recent years, studies have increasingly explored microRNAs as biomarkers and treatment interventions for AD. This study identified a novel microRNA termed miR-25802 from our high-throughput sequencing dataset of an AD model and explored its role and the underlying mechanism. The results confirmed the miRNA properties of miR-25802 based on bioinformatics and experimental verification. Expression of miR-25802 was increased in the plasma of AD patients and in the hippocampus of APP/PS1 and 5 × FAD mice carrying two and five familial AD gene mutations. Functional studies suggested that overexpression or inhibition of miR-25802 respectively aggravated or ameliorated AD-related pathology, including cognitive disability, Aß deposition, microglial pro-inflammatory phenotype activation, and neuroinflammation, in 5 × FAD mice and homeostatic or LPS/IFN-γ-stimulated EOC20 microglia. Mechanistically, miR-25802 negatively regulates KLF4 by directly binding to KLF4 mRNA, thus stimulating microglia polarization toward the pro-inflammatory M1 phenotype by promoting the NF-κB-mediated inflammatory response. The results also showed that inhibition of miR-25802 increased microglial anti-inflammatory M2 phenotype activity and suppressed NF-κB-mediated inflammatory reactions in the brains of 5 × FAD mice, while overexpression of miR-25802 exacerbated microglial pro-inflammatory M1 activity by enhancing NF-κB pathways. Of note, AD-associated manifestations induced by inhibition or overexpression of miR-25802 via the NF-κB signaling pathway were reversed by KLF4 silencing or upregulation. Collectively, these results provide the first evidence that miR-25802 is a regulator of microglial activity and establish the role of miR-25802/KLF4/NF-κB signaling in microglia-mediated neuroinflammation, suggesting potential therapeutic targets for AD.
Assuntos
Doença de Alzheimer , MicroRNAs , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias , Transdução de Sinais/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cinamatos , Triazóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , MasculinoRESUMO
As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.
Assuntos
Conservadores da Densidade Óssea , Osteoporose , Idoso , Camundongos , Humanos , Animais , Osteogênese , Preparações Farmacêuticas/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Peptídeos/metabolismo , Diferenciação Celular , Osteoblastos/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Proteína Morfogenética Óssea 2/metabolismoRESUMO
Osteoporosis is a multifaceted skeletal disorder characterized by reduced bone mass and structural deterioration, posing a significant public health challenge, particularly in the elderly population. Treatment strategies for osteoporosis primarily focus on inhibiting bone resorption and promoting bone formation. However, the effectiveness and limitations of current therapeutic approaches underscore the need for innovative methods. This review explores emerging molecular targets within crucial signaling pathways, including wingless/integrated (WNT), bone morphogenetic protein (BMP), hedgehog (HH), and Notch signaling pathway, to understand their roles in osteogenesis regulation. The identification of crosstalk targets between these pathways further enhances our comprehension of the intricate bone metabolism cycle. In summary, unraveling the molecular complexity of osteoporosis provides insights into potential therapeutic targets beyond conventional methods, offering a promising avenue for the development of new anabolic drugs.
Assuntos
Osteogênese , Osteoporose , Transdução de Sinais , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Animais , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Hedgehog/metabolismo , Terapia de Alvo Molecular , Receptores Notch/metabolismoRESUMO
We have updated the email addresses of Li Zeng and Hailun Jiang as the two authors' previous email addresses are no longer in use [...].
RESUMO
Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5 (GAS5) is a member of the 5'-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease (5×FAD) mice, APPswe/PSEN1dE9 (APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p (miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta (GSK-3ß) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression in an Argonaute 2-induced RNA silencing complex (RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3ß and PTEN cascades with a feedforward PTEN/protein kinase B (Akt)/GSK-3ß linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3ß/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3ß/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
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One-for-all phototheranostics based on a single molecule is recognized as a convenient approach for cancer treatment, whose efficacy relies on precise lesion localization through multimodal imaging, coupled with the efficient exertion of phototherapy. To unleash the full potential of phototheranostics, advancement in both phototheranostic agents and light delivery methods is essential. Herein, an integrated strategy combining a versatile molecule featuring aggregation-induced emission, namely tBuTTBD, with a modified optical fiber to realize comprehensive tumor diagnosis and "inside-out" irradiation in the orthotopic breast tumor, is proposed for the first time. Attributed to the intense donor-acceptor interaction, highly distorted conformation, abundant molecular rotors, and loose intermolecular packing upon aggregation, tBuTTBD can synchronously undergo second near-infrared (NIR-II) fluorescence emission, photothermal and photodynamic generation under laser irradiation, contributing to a trimodal NIR-II fluorescence-photoacoustic (PA)-photothermal imaging-guided phototherapy. The tumor treatment is further carried out following the insertion of a modified optical fiber, which is fabricated by splicing a flat-end fiber with an air-core fiber. This configuration aims to enable effective in situ phototherapy by maximizing energy utilization for therapeutic benefits. This work not only enriches the palette of NIR-II phototheranostic agents but also provides valuable insight for exploring an integrated phototheranostic protocol for practical cancer treatment.
RESUMO
[This corrects the article DOI: 10.3389/fphar.2020.00205.].